Rh-Catalyzed C–H Activation/Cyclization for the Synthesis of Functionalized Indolizino[2,3- b ]quinolinone Derivatives

Abstract

A novel Rh(III)-catalyzed method has been established for the concise synthesis of highly functionalized indolizino[2,3-b]quinolinone derivatives (IZQLOs). This strategy proceeds through a complex cascade reaction between N-pyridin-2-yl enaminones and pyridotriazoles, involving traceless directing group-assisted C–H activation, β-carbon activation of enaminone, and the formation of an oxidized N–C bond to construct the key pyrrole ring framework, followed by intramolecular cyclization to form the lactam. The reaction sequence is flexible, allowing either initial formation of the pyrrole ring, followed by construction of the six-membered pyrimidinone ring, or vice versa. This one-pot process efficiently forges three new bonds, one C–C and two C–N, to build the complex polycyclic frameworks of pyrido[1′,2′:1,2]pyrimido[5,4-a]indolizin-13-ones 3, under [Cp*RhCl2]2 catalysis with 1-AdCO2H as an additive in DCE at 120 °C. Moreover, by employing ortho-halo-substituted enaminones in the presence of NaOAc at 100 °C, the reaction pathway can be redirected to exclusively afford another class of indolizino[2,3-b]quinolinone derivatives 4. This intramolecular SNAr transformation enables efficient and combinatorial access to a diverse array of biologically relevant complex structures based on the IZQLO scaffold.